The present invention relates to a proliferation inhibitor of Helicobacter pylori bacteria comprising an N-acetylglucosaminyl beta-linked monosaccharide derivative, which can inhibit the proliferation of Helicobacter pylori bacteria as a causative microorganism for diseases such as peptic ulcers, gastric cancers and so on.
Helicobacter pylori (H. pylori) bacteria is a bacteria responsible for peptic ulcers and chronic gastritis (Marshall B. J. et al., Lancet, Vol. I, p. 1311-1315 (1984) and Peek R. M. Jr. et al., Nature Reviews Cancer, Vol. 2, p. 28-37 (2002)). It has been said that the persons infected with H. pylori bacteria would reach almost a half of the world population.
H. pylori bacteria inhabits in the superficial mucus secreted from the surface layer of the gastric mucous, but never inhabits in the mucous and the glandular mucus secreted from the mucous deep layer. This glandular mucus inherently contains a sugar chain derived from GlcNAc alpha 1-4Gal beta-group-containing O-glycan having a N-acetyl-glucosamine alpha residue (alpha GlcNAc reside) and a galactose residue (Gal residue). For this reason, the foregoing fact would suggest that the sugar chain may protect the gastric mucous from the infection with H. pylori bacteria.
The inventors of the present invention found out that a sugar chain of glycoproteins which are each linked with a core binary-branched O-glycan having an alpha GlcNAc residue at the non-reduced terminal can substantially inhibit the proliferation of H. pylori bacteria and also that this inhibition of the proliferation is achieved by an enzyme activity inhibition of cholesterol alpha glucosyl transferase (CHL alpha GcT) (Hirai Y. et al., Journal of Bacteriology, Vol. 177, p. 5327-5333 (1995)) which exists only in Helicobacters embracing H. pylori bacteria (Kawakubo M. et al., Science, Vol. 305, p. 1003-1006 (2004)). H. pylori bacteria essentially requires the glucosyl cholesterol components (CGL) for the proliferation, but it cannot synthesize the CGL by itself. Accordingly, it is said that H. pylori bacteria takes in cholesterols from the external world and adds glucose to the region in the proximity to the membrane of the bacterial cell to thus construct the cell wall. In this respect, it would thus be estimated that the foregoing sugar chain of glycoproteins which are each linked with O-glycan carrying the alpha GlcNAc residue has an ability to inhibit the construction of such cell wall, and thus it is expected to be applied to a specific proliferation inbihitor of H. pylori bacteria. However, such complicated sugar chain of glycoproteins having high-molecular weight has to be prepared through multiple troublesome steps under a reaction condition which cannot be fully controlled resulting to require extensive manufacturing facilities and great expense. Therefore, it is not practicable.
Moreover, Japanese Patent Provisional Publication (Translation of PCT Application) No. 2003-517015, discloses Helicobacter pylori bacteria-binding substances as oligosaccharides comprising Gal beta 1,3 GlcNAc structure. However, such substances are polysaccharides and have quite complicated structure resulting to require multiple steps for preparation which do not permit the mass production of the same.
On the other hand, the presently used methods for treating patients infected with H. pylori bacteria are not ones which make use of these sugar chains, but they mainly comprise the step of eradicating bacterial cells through the simultaneous use of the following three kinds of drugs: a kind of proton pump-inhibitor and two kinds of antibiotics. In the medical treatment with which the three kinds of drugs are combined, problems further arise such that this treatment may induce the generation of resistant bacteria to thus cause the recurrence of the infectious disease and that they may cause side effects.
Due to recent increasing concern over health maintenance and harmlessness of beverages, foods or medical preparations, development of a safe proliferation inhibitor of H. pylori bacteria having a simple and natural structure which can be continuously eaten, drunk or administrated is desired.
The inventors of the present invention found out that an N-acetylglucosaminyl alpha-linked monosaccharide derivative has a significant effect on inhibiting the proliferation of H. pylori bacteria and already filed a patent application (WO2008/084561).
Development of further significant proliferation inhibitor of H. pylori bacteria is desired.